Patients with severe beta thalassemia or sickle cell anemia would benefit significantly if HbF production could be consistently augmented. The imbalance in globin synthesis characteristic of thalassemia could be partially corrected by increased gamma globin synthesis. Reduction of intracellular HbS concentration by replacement with HbF reduces the polymerization potential of intracellular sickle hemoglobin, decreasing the sickling "propensity" of red cells from such individuals. Several classes of substances stimulate HbF synthesis including cytotoxic agents (e.g. hydroxyurea), hematopoietic growth factors (erythropoietin) and agents that modify DNA or chromatin structure (e.g. 5-Azacytidine or sodium butyrate, respectively). Two patients have been treated for more than five years with monthly infusions of 5-Azacytidine, each lasting 3-4 days with improvement in hemoglobin level, and in one patient, elimination of the red cell transfusion requirement. The other patient who could not tolerate transfusions because of multiple allo- and auto- antibodies, experienced an increase in hemoglobin concentration from 3.0 to 5.5 gm/dl on 5-Azacytidine. Addition of phenylbutyrate administered orally each day resulted in a further increase in hemoglobin level to 6.5-7.0 gm/dl.